Target Validation Information
Target ID T40097
Target Name Mitogen-activated protein kinase 8
Target Type
Clinical Trial
Drug Potency against Target AM-111 Drug Info IC50 < 500 nM [552998]
NM-PP1 Drug Info IC50 = 140 nM [529039]
N-(6-ethoxypyridin-2-yl)acetamide Drug Info IC50 = 750 nM [528237]
2-(2-(butylamino)pyrimidin-4-ylamino)benzoic acid Drug Info IC50 = 2600 nM [528524]
2-(2-propoxypyrimidin-4-ylamino)benzoic acid Drug Info IC50 = 2300 nM [528524]
2-(2-(phenylamino)pyrimidin-4-ylamino)benzamide Drug Info IC50 = 590 nM [528524]
2-(2-(pentyloxy)pyrimidin-4-ylamino)benzoic acid Drug Info IC50 = 1100 nM [528524]
N-(4-amino-5-cyano-6-phenylpyridin-2-yl)acetamide Drug Info Ki = 1900 nM [528237]
N-(4-amino-6-butoxy-5-cyanopyridin-2-yl)acetamide Drug Info IC50 = 2100 nM [528237]
2-(2-sec-butoxypyrimidin-4-ylamino)benzoic acid Drug Info IC50 = 700 nM [528524]
AS-601245 Drug Info IC50 = 2600 nM [529039]
N-(4-amino-5-cyano-6-ethoxypyridin-2-yl)acetamide Drug Info IC50 = 840 nM [528318]
2-(2-phenoxypyrimidin-4-ylamino)benzoic acid Drug Info IC50 = 300 nM [528524]
2-(2-butoxypyrimidin-4-ylamino)benzoic acid Drug Info IC50 = 1900 nM [528524]
CC-401 Drug Info IC50 = 10000 nM [552744]
Action against Disease Model AM-111 AM-111 blocked JNK mediated phosphorylation and activation of transcription factors c-Jun and c-Fos. AM-111 has been shown to prevent loss of hearing using a guinea pig model inthe setting of systemic aminoglycoside administration as well as in the setting of acute acoustic tra uMa. Hearing preservation has also been noted with AM-111 when given after exposure to impulse noise tra uMa in chinchillas. [552990] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Combined JNK1/JNK2 deficiency drastically increased basal glycerol release, whereas individual JNK1- or JNK2-deficiency had no effect, indicating that JNK1/JNK2-deficiency enhances basal lipolysis, whereas the alternate subtype compensates for a single JNK subtype deficiency in the regulation of basal lipolysis. The profoundly increased glycerol release associated with JNK1/JNK2-deficiency was not accompanied by a concomitant increase in NEFA release over time. In addition, JNK1-deficiency, but not JNK2-deficiency, drastically decreased NEFA release as compared with thatin JNK-intact cells, a result of increased NEFA re-esterification. In microarray, quantitative RT-PCR and western blotting, JNK1-, JNK2- and JNK1/JNK2-deficiencies selectively upregulated many genes involved in NEFA management, without affecting the expression of genes involved in insulin signalling. Assays using reporter genes driven by peroxisome proliferator-activated receptor gamma (PPAR-gamma)-responsive promoters indicate distinct roles for JNK1 and JNK2 in regulating the transcriptional effects of PPAR-gamma.While JNK1 and JNK2 have shared roles in the regulation of basal lipolysis, JNK1 has a more profound role in supporting baseline NEFA release. Inhibition of JNK1 activity in adipocytes has potential therapeutic uses for management of elevated circulating NEFA levels at the onset of insulin resistance. [552998]
References
Ref 552998c-Jun N-terminal kinase (JNK) signaling: recent advances and challenges. Biochim Biophys Acta. 2010 Mar;1804(3):463-75. doi: 10.1016/j.bbapap.2009.11.002. Epub 2009 Nov 10.
Ref 529039Biochem J. 2007 Dec 15;408(3):297-315.The selectivity of protein kinase inhibitors: a further update.
Ref 528237J Med Chem. 2006 Jun 15;49(12):3563-80.Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity.
Ref 528524Bioorg Med Chem Lett. 2007 Feb 1;17(3):668-72. Epub 2006 Nov 2.Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies.
Ref 528524Bioorg Med Chem Lett. 2007 Feb 1;17(3):668-72. Epub 2006 Nov 2.Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies.
Ref 528524Bioorg Med Chem Lett. 2007 Feb 1;17(3):668-72. Epub 2006 Nov 2.Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies.
Ref 528524Bioorg Med Chem Lett. 2007 Feb 1;17(3):668-72. Epub 2006 Nov 2.Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies.
Ref 528237J Med Chem. 2006 Jun 15;49(12):3563-80.Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity.
Ref 528237J Med Chem. 2006 Jun 15;49(12):3563-80.Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity.
Ref 528524Bioorg Med Chem Lett. 2007 Feb 1;17(3):668-72. Epub 2006 Nov 2.Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies.
Ref 529039Biochem J. 2007 Dec 15;408(3):297-315.The selectivity of protein kinase inhibitors: a further update.
Ref 552990AM-111 prevents hearing loss from semicircular canal injury in otitis media. Laryngoscope. 2010 Jan;120(1):178-82. doi: 10.1002/lary.20759.
Ref 528318J Med Chem. 2006 Jul 27;49(15):4455-8.Discovery of potent, highly selective, and orally bioavailable pyridine carboxamide c-Jun NH2-terminal kinase inhibitors.
Ref 528524Bioorg Med Chem Lett. 2007 Feb 1;17(3):668-72. Epub 2006 Nov 2.Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies.
Ref 528524Bioorg Med Chem Lett. 2007 Feb 1;17(3):668-72. Epub 2006 Nov 2.Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies.
Ref 552744Inhibitors of c-Jun N-terminal kinases: JuNK no more? Biochim Biophys Acta. 2008 Jan;1784(1):76-93. Epub 2007 Oct 11.

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